ABSTRACT Aerobic glycolysis dominates energy metabolism in photoreceptor neurons. In aerobic glycolysis, most of the glucose a cell consumes gets converted into lactate, even when O2 is present. Aerobic glycolysis has been linked to anabolic activities that support robust growth in cancer cells. This has led to the hypothesis that enhancing aerobic glycolysis will make photoreceptors more robust and resistant to stresses caused by genetic deficiencies. Recent work supports this hypothesis. The transcription repressor Sirtuin 6 (Sirt6) has several activities, one of which is to repress expression of glycolytic genes. Sirt6 deficiency increases expression of key metabolic enzymes that carry out aerobic glycolysis. Remarkably this slows degeneration of rods and cones caused by a PDE6b mutation. The project in this proposal will identify metabolic gene{s) that most efficiently enhance photoreceptor survival. We will use zebrafish as a model organism. Specifically, we will increase expression in cones of key metabolic enzymes that enhance glycolytic activity and assess, using imaging strategies we developed, the slowing of degeneration caused by PDE6-deficiency. Initially, we will focus on enzymes most likely to be rate-limiting; Glut-1, hexokinase, pyruvate kinase, phosphofructokinase, pyruvate dehydrogenase kinase and lactate dehydrogenase (Aim 1). We then will use metabolomics to identify specific metabolic changes that are linked to prolonged photoreceptor survival (Aim 2). Overall, our studies will provide basic metabolic information needed to understand how enhancing aerobic glycolysis can promote photoreceptor survival. Future studies based on these findings will be aimed at developing therapeutic strategies that enhance metabolic features that promote photoreceptor viability.